17alpha-amino-progesterone and intermediates in the production thereof



United States Patent 3,487,076 17a-AMINO-PROGESTERONE AND INTERMEDI- ATES IN THE PRODUCTION THEREOF David B. R. Johnston, Warren, Arthur A. Patchett, Cranford, and Thomas B. Windholz, Westfield, N.J., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Sept. 1, 1967, Ser. No. 664,905 Int. Cl. C07c 169/34, 167/34, 167/36 US. Cl. 260-23955 9 Claims ABSTRACT OF THE DISCLOSURE Novel l7u-aminoprogesterones are prepared by (1) ring opening of an N-alkanoyl-16a,17a-iminopregn-5-en- 3fl-ol-20-one to yield 170: alkanoylaminopregn-5-en-3pol-s20-one; (2) Oppenauer oxidation of the latter compound to 17a-alkanoylaminopregn-4-ene-3,20-dione; and (3) conversion of the .l7a-alkanoylarnino derivative to the 17a-aminopregn-4-ene-3,ZO-dione. The 60c methyl, 16-methyl, 6oc-Chl0l'0 and 6a-fluoro derivatives are prepared as well as the M' -analogues thereof.

I This invention relates to 17a-aminoprogesterones, and to methods for the synthesis thereof. The compounds of the present invention have the following structure:

on C:

j --NHRa l W R] 0Q. I f

' I V Me 3,487,076 Patented Dec. 30, 1969 and the M' -analogues thereof; where R is hydrogen or methyl; R is hydrogen or lower alkanoyl; and R is hydrogen, methyl or halo.

The above compounds are aldosterone antagonists, have antihor-monal activity, and are useful in the control and regulation of the female cycle.

Illustrative of the above-defined compounds, but not limited thereto, are the following:

The synthetic route for preparing the 171! aminoprogesterone compounds of our invention involves three basic steps:

( 1) ring opening of an N-alkanoyl-16a,17u-iminopregn- 5-en-3B-ol-20-one (I) to yield the l7a-alkanoylaminopregn-5-en-3B-ol-20-one (II);

(2) oxidation of compound (II) to the corresponding 17a-alkanoylaminopregn-4 ene-3,20-dione (111a); and

(3) conversion of the 17a-alkanoylaminopregn-4-ene-3,-

Z'O-dione (llIa) to the 17a aminopregn-4-ene-3,20- dione (IHb). I v 7 These compounds are shown on Flow Sheet A.

FLOW SHEET A A $113 (EH3 (1:0 O=R4 i "NHR: C] -w R1 Iwv R1 C l a i LO I it, III R5 IV H OH (0) H4 41: R =H According to Step A of the process of our invention, an N-al'kanoyl-l6a,17a-iminopregn-5-en-3,8-ol-20-one (I) is heated with an alkali metal salt of a mercaptan at an elevated temperature in an inert atmosphere to afford the corresponding 165-R S-17a-alkanoylaminopregnen-5 en-3B-ol-20-one (Ila). The preferred RqSH mercaptan is thiophenol. Other mecaptans which may be used have the formula RqSH, where R, is alkyl, cycloalkyl, phenyl or benzyl; or phenyl or benzyl substituted by lower alkyl or lower alkoxy groups. Examples of such mercaptans are n-butyllnercaptan, cyclohexylmercaptan, benzylmercaptan, thiophenol, 0-, m-, or p-rnethoxythiophenol, and 0-, m-, or p-mercaptotoluene.

Temperatures in the range of about 70 to 200 C. are employed. The refluxing temperature of the particular solvent system employed is preferred, although the actual temperature used is not critical. Preferred solvents for the reaction are monoor di-alcohols having four or more carbon atoms which boil within the temperature range. Such solvents include teritary butyl alcohol, secondary amyl alcohol, cyclopentanol and the like.

A solution of compound (11a) is then treated with Raney nickel and an unsaturated hydrocarbon at an elevated temperature in an inert atmosphere to afford the 17 a-alkanoylaminopregn-S-en-3 fl-ol-20 one (11b). The preferred solvent is isopropyl alcohol, although other C C alcohols such as ethanol, isobutanol, or t-butanol, can be used. Cyclohexene, cyclopentene or other unsaturated cycloalkenes or alkenes are suitable for this reaction. The reaction is carried out at temperatures within the range of 70-l20 C. for about two to forty minutes, the refluxing temperature of the particular solvent system generally being preferred.

Compounds (IIa) and (1115) can be acylated to the corresponding 3 8-alkanoyl-derivative (He) and (IId) by conventional methods, using an alkanoyl halide or anhydride in the presence of an organic base.

In Step B of our process, the 17a-a1kanoyl-aminopregn-5-en-3fl-ol-20-one (IIb) is oxidized to the 17u-alkanoylaminopregn-4-en-3,20dione (IIIa). The oxidation preferably takes place using the procedure known commonly in the art as the' Oppenauer oxidation, employing aluminum isopropoxide and cyclohexanone, in an inert or- Oxidation with this reagent is accomplished by adding a ganic solvent, preferably benzene, toluene or xylene solution of aluminum isopropoxide in an aromatic hydrocarbon to a solution of the steroid and cyclohexanone in an aromatic hydrocarbon. Conveniently, the mixture is dried by azeotropic distillation. The mixture is then refluxed for 2-4 hours. After hydrolysis of the'reaction mixture, the product is recovered by filtration, evaporating the solvent under reduced pressure, and crystallizing the residue from a solvent, such as a mixture of ether and methanol or methylene chloride. In Step C of our process, the l7a-al'kanoylaminopregn-4-ene-3,20- dione (IIIa) is converted to the l7a-aminopregn-4-ene- 3,20-dione (IIIb). This conversion is preferably carried out indirectly by a circuitous route involving several procedures, rather than by direct hydrolysis of the 17a-alkanoyl group. In the preferred procedure, the 17a-alkanoylaminopregn-4-ene-3,20-dione (IIIa) is converted to the 3-monodioxolane (IVa), which is then reduced at C to give (IVb), followed by basic hydrolysis at C to afford (IVc), and finally oxidation back to the 3-keto-derivative (IIIb). In-this procedure, the 3-keto group of 17walkanoylaminopregn-4-ene-3,20-dione (IIIa) is protected by forming the 3-ethylenedioxy-derivative. This derivative is prepared by reaction of a solution of the steroid in a solvent such as benzene, toluene or xylene, with an equivalent amount of ethylene glycol and a strongly acidic catalyst such as p-toluene-sulfonic acid, dinit-robenzoic acid and the like, for about 8-12 hours. The product may be recovered by washing with aqueous sodium bicarbonate, drying and concentrating under vaccum.

The 3-keto group may also be converted into the 3- ethylenedioxy-derivative by exchange dioxolanation, which involves acid-catalyzed transfer of the ethylene glycol portion of simple 2,2-dialkyl-1,3-dioxolanes, such as 2,2-dimethyl-1,3-dioxolane (acetone ethyleneketal) or, better, 2-methyl-2-ethyl-1,3-dioxolane (butanone ethyleneketal), with the 3-ketone steroid either in an inert solvent, such as benzene, or simply in excess reagent. Other cyclic ketal derivatives, such as methylenedioxy, propylenedioxy, or butylene-dioxy derivatives, can also be used for protecting the ketone group at C The 17a-alkanoyl-3,3-ethylenedioxypregn-S-en-205-one (IVa) is then reduced to the 17rx-alkanoy1amino-3,3-ethylenedioxypregn-S-en-20-01 (IVb) by heating a solution of the steroid with a reducing agent, preferably sodium borohydride, for 1-3 hours. The 17a-alkanoyl group is then hydroylzed by heating a solution of the steroid with an inorganic base, such as potassium hydroxide, sodium hydroxide and the like, for 10-20 hours to give compound (IVc).

The amino-3,3-ethylenedioxypregn-S-en-ZOE-ol (IVc) is then oxidized with CrO to give the 170L'3I1'1l1'l0- pregn-4-ene-3,20-dione (IIIb). Suitably, the steroid is dissolved in an organic base, such as pyridine or quinoline, CrO is added, and the mixture is permittedto stand for 6-10 hours at room temperature.

- Flow Sheet B shows the conversion of the 17a-aminopregn-4-ene-3,20-dione compounds (IIIb) into the cor- 6 3,20-dione, (3) epimerizing the 6fl-fluoro-derivative present in the mixture to the 17a-acylamino-6a-fluoropregn- 4-ene-3,20-dione, and (4) converting the 17a-acetylamino- 6a-fluoropregn-4-ene-3,20-dione into the 17a-arnino-6afluoropregn-4-ene-3,20-dione, following the procedures responding 6-halo and/or the pregna-4,6-diene deriva- 5 described above in Step C for converting compound tives. (IIIa) into compound (IIIb).

FLOW SHEET B r (IJ s 3 T T ---NHRa 'IIIb VI HO R1R =H or CH3 R1R5=H or CH lR3=H E 0:0 --NHR3 l VIII I IX RqO- Rr=Hor on, 0: R =Hor CH R =alkanoyl l Ru=alkyl Y t x: Y

om I 0H ""NHRa I e i N I vrrr X o: 1 R1=H or CH3 0: R =H or CH3 Ra -H or alkanoyl v The 17waminopregna-4,6-diene-3,20-dione, or the 6- methyl, 16E-methyl or 6,16g-dimethyl-derivatives thereof (VI), can be prepared by heating a mixture of the 1701- aminopregnen-4-ene-3,20-dione (IIIb) and chloranil with glacial acetic acid and an alkanol such as t-butyl alcohol, secondary amyl alcohol and the like.

The 17a-amino-6-chloropregna-4,6-diene-3,20-dione, or the l6g-methyl-derivative thereof (X), is prepared by treating a solution of the 17 ot-aminopregna-4,6-diene-3,20- dione with an ethereal solution of monoperphthalic acid at room temperature for -70 hours, protected from moisture to give the 17a-amino-6a,7a-epoxypregn-4-ene- 3,20-dione. The latter compound, in glacial acetic acid solution, is then reacted with HCl to yield the 17x-amino- 6-chloropregna-4,6-diene-3,20-dione.

The 17a-amino-6-fiuoropregn-4-ene-3,20-dione, or the l6g-rnethyl-derivative thereof (VIII), is prepared by (1) converting the 17u-acylaminopregn 4 ene 3,20 dione (IIIa) into the 17a-acylamino-3-ethoxypregna-3,S-diene- 20-one by treatment with a strong acid such as p-toluenesulfonic acid, dinitrobenzenesulfonic acid and the like, (2) passing perchloryl fluoride into a solution of the 170:.- acylamino-3-ethoxypregna 3,5-dien-20-one to yield a mixture of the 17aand 17/3-acylamino-6,8-fluoropregn-4-ene- EXAMPLE 1 17a-acetylamino-16g-phenylthiopregn 5-en 3larol 2:0-one (Ila) i j A mixture of 2.8 g. (7.5 mM.) ofv N-acetyl-16a,17a. iminopregn-S-en3[3-ol-20-one (I), obtainedaccording to the process described in G. Drehfahl et al., Chem. Ber. 98, 186 (1965), 14 ml. of t-butyl alcohol, and 1.4 ml, of freshly distilled thiophenol (about 12 mM.), is stirred and heated, giving a clear solution. To this is added 3.0 ml. of 1.1 M potassium t-butoxide (in t-butyl alcohol), and the mixture is gently refluxed overnight under nitrogen. Upon cooling and stirring, a paste is obtained which is filtered. The filter cake is washed several times with ether, then recrystallized from chloroform/methanol to give 1.81 g. of 11a. Chromatography of the mother liquo rs on silica gel, and eluting with 2-4% methanol in chloroform, atfords another 0.3-0.4 g. of 11a after recrystallization. I

The analytical sample, recrystallized several times from chloroform/methanol, has M.P. -2'83 284 C.;.-I.R'.'.3.03 (NH, OH), 5.81 (C 0), 5.97 (CONH), 6.54 (NH) ,u (pyridine); UV. 259 mg (6,500) (MeQI I) (8); N. M.R.

7 2.66 (SC H 4.7 (C -H), 8.08 (AcN, C -H), 8.95 and 9.05 (C H and C -H) a- (DMSO).

Analysis.Calcd. for C H O NS: C, 72.31; H, 8.16; N, 2.91; S, 6.66. Found: C, 72.58; H, 7.86; N, 3.09; S, 6.39.

Acetylation of Ila is carried out by heating with acetic anhydride and pyridine. The product, 3fl-acetoxy-17aacetylamino-16B-phenylthiopregn-5-en-20-one (IIc) after recrystallization, has an M.P. of 226-228 C.; IR. 2.90 (NH), 5.84 (COO, C 5.98 (CO-NH) ,u. (CHCla); U.V. 259 H111. (6,550) (MeOH) (8); N.M.R. 2.5-2.9 (SC H 4.7 (C -H), 7.89, 7.94, 7.98 (AcO, AcN, C H), 8.91 (C -H), 8.98 (C -H) '1' (CDCI Analysis.-Calcd. for C H NO' S: C, 71.09; H, 7.89; N, 2.68; S, 6.12. Found: C, 71.46; H, 7.89; N, 2.56; S, 6.02.

EXAMPLE 2 17a-acetylaminopregn-S-en-3fi-ol-20-one (111)) A mixture of 1.7 g. of l6g-phenylthio-l7a-acetylaminopregn-5-en-3 3-ol-20-one (Ila) (3.5 mM.), 256 ml. of isopropyl alcohol and 86 ml. of distilled cyclohexene is rapidly added to 12.8 g. of W3 Raney nickel (weighed as a wet centrifuged cake) in a flask equipped with an eflicient stirrer and a reflux condenser under a nitrogen atmosphere. Quick immersion of the flask in an oil bath preheated to approximately 110 C. brings about smooth refluxing in 2-3 minutes. After another minutes of refluxing, the oil bath is replaced with an ice bath, bringing the reaction to room temperature in 3.5 minutes. An aliquot is removed, filtered, evaporated, and the residue examined by U.V.; a distinct shoulder at 253 m is observed; so the mixture is again rapidly brought to reflux and maintained there for another ten minutes followed by rapid cooling. The aliquot now shows only a slight inflection in the U.V. spectrum in the 250-260 mg region. The time required to elfect loss of the chromophore is dependent on several variables including the batch of Raney nickel, the scale of the reaction, and especially upon the efliciency of stirring. The entire reaction mixture is carefully filtered through Celite (an infusorial earth), and the filtrate is evaporated under reduced pressure giving 1.7 g. of foam. Crystallization from methanol gives 0.9 g. of IIb. Repeated recrystallization from methanol gives an analytical sample, M.P. 265-267 C.; I.R. 3.03 (NH, OH), 5.86 (C 0), 6.00 (CONH), 6.62 (NH) u (pyridine); U.V. no significant max. above 220 m N.M.R. 3.95 (NH), 4.6 (C -H), 7.90, 7.98 (AcN, C H), 8.98 (C -H), 9.29 c,, H T (CD01 Analysis.Calcd. for C H NO C, 73.95; H, 9.45; N, 3.75. Found: C, 74.11; H, 9.32; N, 3.86.

Acetylation of IIb is carried out by heating With-acetic anhydride and pyridine. The product, 3B-acetoxy-17aacetylaminopregn-S-en-ZO-one (IId), after recrystallization, has an M.P. of 261-263" C.; I.R. 2.90 (NH), 5.81 (COO), 5.86 (C 0), 6.03 (CONH), 6.75 (NH) a (CHCI3); N.M.R. 4.6 (C H), 7.90, 7.96, 7.98 (A00, AcN, (C -H), 8.96 (C -H), 9.29 (C -H) 1- (CDCI Analysis.-Calcd. for C H NO C, 72.25; H, 8.98; N, 3.37. Found: C. 71.98; H, 8.79; N, 3.67.

The amino group in the above compound (IIb) was shown to be attached to C by conversion to the 20- oxime, followed by Bechmann rearrangement to the known 3fi-acetoxyandrost-5-en-17-0ne in the following procedure.

A mixture of 17a-acetyIaminOpregn-S-en-3B-acetoxy- 20-one (189 mg.), hydroxylamine hydrochloride (304 mg.), and 3.0 ml. of pyridine is heated for 5 hours under nitrogen on a steam-bath, with occasional stirring. The mixture is then poured into water and extracted several times with methylene chloride. The extracts are washed with dilute acid, water, bicarbonate solution, and salt solution, then dried with magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with 1-2% methanol in chloroform; appropriate fractions are combined and crystallized from methylene chloride/ether to give 132 mg. of oxirne.

Repeated recrystallization from methanol aifords material with M.P. 230-233 C.; LR. 2.79, 2.90, 3.02 (NH, OH), 5.82 (COO), 5.99 (CONH), 6.73 (NH) ,u (CHCI N.M.R. 4.6 (C H), 7.97, 8.01, 8.19 (AcO, AcN, C H), 8.98 (C -H), 9.29 (C -H) 1' (CDCI I Analysis.-Calcd. for C H N O C, 69.73; H, 8.90; N, 6.51. Found: C, 70.42; H, 8.82; N, 6.41.

A solution of 55 mg. of oxime in 0.3 ml. of pyridine is cooled to 0 C. and treated with a cooled solution of 196 mg. of toluene sulfonic anhydride in 3 ml. of pyridine. The bright yellow solution is stirred for 45 minutes at 0 C., then treated with 3 ml. of cold water. The mixture is then poured into cold water and extracted repeatedly with methylene chloride. The extracts are washed with dilute acid, water, bicarbonate solution, and salt solution, and then dried with magnesium sulfate, and evaporated under reduced pressure with minimum heating to give 45 mg. of gum. Concentration of a methylene chloride solution and addition of ether gives two crops of solids, plus mother liquors. All are complex mixtures. They are each taken up in 0.1 ml. of pyridine with enough Water to cause clouding, then heated 45 minutes on the steambath, and then taken to dryness under reduced pressure. Percolation of each through a 4 x 12 mm. column of aluminum oxide in benzene, followed by 5 ml. each of benzene, ether, and methanol, removes some dark gummy impurities. The cleanest eluates are combined and cry tallized, giving 16 mg. (40%) of 3/8-acetoxyandrost-5-en-17- one in two crops, identified by thin layer chromatography, M.P., mixed M.P., and LR. comparison with authentic material.

EXAMPLE 3 17a-acetylaminopregn-4-ene-3,20-dione (IlIa) A solution of 1.67 g. of 17cr-acetylaminopregn-5-en-3{3- ol-20-one (Hb) in 70 ml. of toluene and 63 ml. of cyclohexanone is dried by heating until 5-10 ml. of distillate has been collected. The solution iscooled slightly, and

'70 ml. of a 0.66 M solution of aluminum isopropoxide in toluene is carefully added. Refluxing, with eflicient stirring, is resumed for three hours. After cooling and adding 1-2 ml. of water, the mixture is vigorously stirred for 5-10 minutes; a second portion of water is then added and stirring is repeated. The suspension is mixed with a small portion of magnesium sulfate and Celite (an infusorial earth), and then filtered through Celite. The filtrate is evaporated under reduced pressure and the residual cyclohexanone is removed by repeated distillation of small portions of water from the residue under reduced pressure. Crystallization from methanol/ ether, or methylene chloride/ether gives 1.09 g. of HM. Recrystallization from methylene chloride/ ether gives an analytical sample, M.P. 283-286" C. (dec.); LR. 2.90, 2.97 (NH), 5.88 (C 0), 6.06 (C 0, CO-NH); 6.66 (NH) ,u. (CHCl U.V.; 241 m (16,700) (MeOH); N.M.R. 4.37 (Cy-11), 7.89, 8.00 (AcN, C H), 8.79 (C H), 9.27 (C H) 1- (CDCI Analysis.Calcd. for C H O N: C, 74.36; H, 8.95; N, 3.77. Found: C, 74.15; H, 8.86; N, 3.77.

Somewhat better over-all conversions from Ila to IIIa are obtained if the oxidation is carried out directly on the total desulfurization product (Example 2) without isolation of pure IIb.

EXAMPLE 4 17rx-acetylamino-3,3-ethylenedioxypregn-S-en-20-one (IVa) A mixture of 102 mg. of l7a-acetylaminopregn-4-en-3, 20-dione (IIIa), 5 ml. of benzene, 10 mg. of p-toluene sulfonic acid monohydrate, and 0.3 ml. of ethylene glycol is refluxed for 18 hours in a flask equipped with a Dean- Stark water separator. The-reaction mixture is poured into sodium bicarbonate solution and. extracted with methylene chloride. The extract is dried with magnesium sulfate, and evaporated under reduced pressure. Crystallization of the residue from ether gives 61 mg. of (Na); LR. 2.90 (NH), 5.88 (C 6.02 (CO-NH), 6.76 (NH) [1. (CHCl N.M.R. 4.6-4.7 (C H), 6.06 (OCH CH -O), 7.89, 7.99- (AcN, 0 -11), 8.96 (C .H), 9.29 (C -H) 7 (CHCl EXAMPLE l7a-acetylamino-3 ,3-ethylenedioxyregn-S-en-20-ol A mixture of 325 mg. of 17a-acetylamino-3,3 ethy1enedioxypregn-5-en20-one (IVa), 330 mg. of sodium borohydride and 11.6 ml. of ethanol is refluxed for 1.5 hours, cooled, and poured into an excess of aqueous sodium dihydrogen phosphate. The mixture is extracted several times with ethyl acetate, and the combined extracts are washed with sodium chloride solution and dried with magnesium sulfate. Evaporation under reduced pressure afifords'308 mg. of crude 17u-acetylamino-3,3-ethylenedioxy-pregn-5-en-20-ol (lVb). Recrystallization from ether gives IVb, M.P. 2102-l2 C.; LR. 3.00 (OH), 3.11 (NH), 6.10 (CO'-NH), 6.7 (NH) a (Nujol).

EXAMPLE 6 3,3-ethylenedioxy-17a-a'minopregn-5-en-20g-ol (lVc) Without further characterization, the entire reaction product (Example 5) is dissolved in 30 ml. of methanol, along with 2.2 g. of potassium hydroxide, and the solution is refluxed under nitrogen for 19 hours. The mixture is poured into sodium chloride solution and extracted several times with ethyl acetate; the combined'extracts are then washed with sodium chloride solution, dried with magnesium sulfate and evaporated under reduced pressure to give 234 mg. of crude product. Upon trituration with ether and prolonged standing, a powdery solid (We) is obtained which exhibits a sharp diminution in CONI-I absorption in the LR. relative to that of IVb, and which is used directly in the next reaction.

EXAMPLE 7 3,3-ethylenedioxy-l7a-aminopregn-5 en-20-one (IVd) A cold solution of 52 mg. of 3,3-ethylenedioxy-17aaminopregn-5-en-20i ol (IVc) in 0.5 ml. of pyridine is added to a cold mixture of46 mg. of CrO in 0.5 ml. of pyridine, and allowed to stand at room temperature overnight. The mixture is dilulted with about 5 ml. of ethyl acetate, shaken vigorously, and centrifuged. The supernatant liquid is removed, and the precipitate repeatedly shaken and centrifuged with 5 ml. portions of ethyl acetate three more times; the combined supernatant fractions are washed with water and salt solution, dried with magnesium sulfate and evaporatedunder reduced pressure to give 38 mg. of gum. Crystallization from methylene chloride/ether affords mg. of 3,3-ethylenedioxyl7a-aminopregn-5-en-20-one (IVa) in two crops. An analytical sample has an M.P. of 228231 C. (dec.); LR. 2.97, 3.03 (N11 5.96 ((3 0), 6.36 (NH2); (Nujol); 5.93 (C 0), 6.29 (N'H2) (CHCl a; N.M.R. 6.06 (O-CH -CH -O), 7.78 (C H), 8.97 (C H), 9.31

Analysis.-Calcd.' for C H O N: C, 73.95; H, 9.45; N. 3.75. Found: C, 74.63; H,-9.24; N, 3.67.

EXAMPLE 8 l7a-aminopregn-4-ene-3,20-dione (lIIb) A solution of 3,3-ethylencdioxy-l7a-arninopregn-5-ene- 20-one (IVd), 21 mg, and l5.5 mg. of p-toluene sulfonic acid monohydrate in 1.0 ml. of acetone is allowed to stand at room temperature overnight; it is then poured into water, made basic with sodium hydroxide, and extracted several times with ethyl acetate. The combined extracts are Washed with water, dried with magnesium sulfate, and evaporated under reduced pressure to give 18 mg. of crystalline 17a aminopregn 4 ene 3,20-dione (Hlb). Recrystallization from methylene chloride/ether gives material with M.P. 169-173 C. (dec.); LR. 2.94 (broad; NH 5.95 (C 0), 6.04 (C 0), 6.23 (NH a (CHCl U.V. max. 241 m (15,600); N.M.R. 4.31 (C --H), 7.84 (C -H), 8.85 (C H), 9.32 (C -H).

Analysis.Calcd. for C H O N: C, 76.55; H, 9.48; N, 4.25. Found: C, 76.61; H, 9.21; N, 4.24.

Assignment of a Not-configuration to the amino group follows from a comparison of the chemical shifts of the C protons in IIIa and IIIb with those in the known amino and hydroxy progesterones and their acetyl derivatives.

That D-homoannulation had not taken place was shown by the normal appearance of the C protons as a singlet at 7.847.

EXAMPLE 9 Following the procedures of Examples 1 to 8, but starting with an equivalent amount of Nacetyl-16;8- methyl-l6tx,17 -iminopregn-5-en 3B-ol-20-one, N-acetyl- 6a-methyl-16a,17a-iminopregn-5-en-3B-ol-20-one, or N- acetyl-6a,l6fi-dimethyl-16a,17a-iminopregn-5-en-3[3-01-20- one in place of N-acetyl-16a,17a-iminopregn-5-en-3B-ol- 20-one, the following intermediates and end-products are obtained: 17a-acetylamino-165-methyl-165-phenylthiopregn-5-en-3fiol-20-one 17 a-acetylamino-6a-4methyll 6g-phenylthiopregn-5-en-3[3- ol-20-one l7u-acetylamino-6a,1 6g-dimethy1-l 6-phenylthiopregn-5- en-3/8-ol-20-one l7a-acetylamino-16g-methylpregn-5-en-3/3-ol-20-one l7a-acetylamino-6u-methylpregn-5-en-3B-ol-ZO-one l7a-acetylamino-6a,16i-dimethylpregn-5-en-3B-ol-20-one 17 a-acetylamino-l 65-methylpregn-4-en-3 ,20-dione 17u-acetylamino-6a-methylpregn-4-ene -3,20-dione 17a-acetylamino-6a,16g-dimethylpregn-4ene-3,20-dione 17a-a'cetylamino-3,3-ethylenedioxy-165-methylpregn- 5-en-20-one 17u-acetylamino-3,3-ethylenedioxy-6a-methylpregn- 5-en-20-one 17 u-acetylamino-3 ,3 -ethylenedioxy-6u, 1 6.5-dimthy1pregn- 5-en-20-one 17m-acetylamino-3,3-ethy1enedioxy-l6g-methylpregn- 5-en-205-ol 17a-acetylamino-3,3-ethylenedioxy-fia-methylpregn- 5-en-20g-ol 17 a--acetylamino-3 ,3 -ethylenedioxy-6u, 165-dimethylpregn- 5-en-20g-ol 3,3-ethylenedioxy-16$-methyl-17a-aminopregn-5-en-20-ol 3,3-ethylenedioxy-6a-methyl-l7a-aminopregn-5-en-20-ol 3 ,3 -ethylenedioxy-6a, 16.5-dimethyl-17a-aminopregn-5- en-20-ol 3,3-ethylenedioxy-16-methyl-17a-aminopregn-5-en- 20-one 3,3-ethylenedioxy-6a-methyl-17a-aminopregn-5-en-20-one 3,3-ethylenedioxy-6a,16.5-dimethyl-17a-aminopregn- 5-en-20-one 17a-amino-16g-methylpregn-4-ene-3,20-dione 17a-amino-6u-methylpregn-4-ene-3,ZO-dione 17 u-ami'no-6a,16&dimethylpregn-4-ene-3,20-dione' The N acetyl 16a,17at iminopregn--en-3fl-20-one starting materials which are substituted by 6a-methyl, 16B- methyl or 6a,l6,8-dimethyl, are obtained in the manner described hereinafter.

A mixture of 3B-acetoxy-6u-methylpregna 5,16-dien- 20-one (10.0 g.), 70 cc. of ethanol and 1 cc. of methoxyamine is refluxed for 12 hours. After cooling and adding 1.75 cc. of methoxyamine, the solvent is distilled off under vacuum and the residue dissolved in ether. On addition of hydrochloric acid, the 3B-acetoxy-6ot-methyl- 16a-methoxyaminopregn-S-en-20-one precipitates.

In accordance with the above procedure, but starting with 35 acetoxy 60:,16 dimethylpregna 5,16-dien-20 one, or the 3,8 acetoxy 16 methylpregna 5,16-dien- 20- one, there is obtained the 3fi-acetoxy-6a,l6.-dimethyl- 165- methoxyaminopregn 5 en 20 one or the 3B- acetoxy 16$ methyl 16$ methoxyaminopregn 5 en- 20-one, respectively.

The 33 acetoxy 6oz methyl 16a methoxyaminopregnen 5 en 20 one, 3 8 acetoxy 6a,16g-dimethyl- 165 methoxyaminopregn 5 en 20 one, or 3B-acetoxy- 16$ methyl 16.5 methoxyaminopregn 5 en 20-one, is then converted into the Got-methyl, 6a,16-dimethyl, or the 16-methyl derivative, respectively, of N-acetyl-l6a, 17ot-iminopregn-5 en 3B ol-20-one, following the procedures described by G. Drefahl et al., Chem. Ber. 98, 186-192 1965 for the conversion of the 35-acetoxy-16amethoxyaminopregn-S-en 20 one to the N-a-cetyl-16a, 17a-iminopregn-5-en-3 8-ol-20-one.

EXAMPLE 10 17ot-aminopregna-4,6-diene-3,20-dione A mixture of 0.16 g. of 17ot-aminopregn-4-ene-3,20- dione (IIIb), 0.30 g. of chloranil, and 0.20 ml. of glacial acetic acid in ml. of t-butyl alcohol is heated under reflux for 16 hours and then cooled, diluted with methylene chloride, and filtered. The filtrate is washed with water, 5% aqueous sodium hydroxide solution, water, and satu rated sodium chloride solution. Evaporation under vacuum affords the product, which is purified by recrystallization.

In accordance with the above procedure, but starting with 17a-amino-6u methylpregn 4 ene-3,20-dione or 1711 amino 6a,l6$-di-methylpregn 4 ene 3,20-dione, in place of 17 m aminopregn 4 ene 3,20-dione, there is obtained the 170: amino 6 methylpregna 4,6-diene- 3,20-dione or 1711 amino 6,165 dimethylpregna 4,6- diene-3,20-dione.

EXAMPLE 11 17a-amino-6-chloropregna-4,6-diene-3,ZO-dione (A) 17oz amino 6u,7m epoxypregn 4 ene 3,20- di0ne.-To a solution of 776 mg. (2 mM.) of 17ot-aminopregna 4,6 diene 3,20 dione in 190 ml. of methylene chloride is added 5 3 ml. of a solution of monoperphth alic acid in ether (containing 48 mg. per ml., 14 mM. of perphthalic acid), and the solution is stirred well and allowed to stand at room temperature for 68 hours protected from atmospheric moisture. The solution is decanted from precipitated perphthalic acid, washed with two 50 ml. portions of saturated aqueous sodium carbonate, two 50 ml. portions of water, and two 50 ml. portions of saturated aqueous sodium chloride, and dried. The solvent is evaporated and the oily residue crystallized on trituration with ether. The precipitate is washed several times with cold ether to aiford the product, which is recrystallized from a mixture of methylene chloride and ether.

(B) 17a amino 6 chloropregna 4,6 diene 3,20- dione.Hydrogen chloride is bubbled into a stirred solution of 195 mg. of 17 a arnino-6a,7u epoxypregn 4-ene- 3,20-dione in 10 ml. of glacial acetic acid over a 10 minute period, and the solution is allowed to stand for 2 hours at room temperature. After resaturation with hydrogen chloride, the solution is allowed to stand an additional two hours and then poured slowly, with stirring, into ml. of ice-water. The aqueous mixture is extracted with chloroform and the extracts are combined, washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and then dried. The solution is evaporated and the residue is purified by chromatography on silica gel using mixtures of ether/ benzene as the eluent to give the 17ot-amino-6-chloropregna-4,6- diene-3,20-dione.

EXAMPLE 12 17ot-amino-6u-fluoropregn-4-ene-3,20-dione 17a-acety1aminopregn 4 ene 3,20 dione (IIIa) (1 g.), dioxane (10 ml.), ethyl formate (1 ml.), and ptoluenesulfonic acid monohydrate (100 mg.) are mixed and stirred for 2 hours at 25 C. To the mixture is added 5 ml. of pyridine, and then ice-water. The reaction mixture is then allowed to stand for 2 hours in the refrigerator, and the precipitate which forms is removed by filtration. The solid is washed with water, dried, and crystallized from a mixture of acetone/hexane to yield 17aacetylamino-3-ethoxypregna-3,5-dien-20-one.

A stream of perchloryl fluoride is passed slowly into a solution of the above product in 500 ml. of thiophenefree benzene at 18-22 C. until 1.2 moles are absorbed to yield 17a-acetylamino-6g-fluoropregn-4-ene-3,20-dione.

A stream of dry hydrogen chloride is passed for two hours through a solution of l g. of the above product in 50 ml. of glacial acetic acid at 18 C. The mixture is poured into 500 ml. of ice-Water. The precipitate is removed by filtration, Washed until neutral, dried, and purified by chromatography to yield l7m-acetylamino-6aalluoropregn-4-ene-3,20-dione.

The 17oz acetylamino-Ga-fluoropregn-4-ene-3,ZO-dione is then converted to the 17tat-amino-6et-fluoropregn-4-ene- 3,20-dione following the procedures of Examples 4-8 for the conversion of l7ot-acetylaminopregnen-4-en-3,20-dione (IIIa) to 17ot-aminopregnen-4-ene-3,20-dione (HIb).

What is claimed is:

1. A compound of the following structure, and the M -analogues thereof:

wherein 2. The compounds of claim 1 where R is fiuoro. 3. The M -analogue of claim 1 where R is chloro. 4. A compound of the structure:

wherein: by treatment with Raney nickel in the presence of an unsaturated hydrocarbon;

(B) oxidizing said l7a-alkanoylaminopregn en-3B- ol-20-one to the 17a-alkanoylaminopregn-4-ene-3,20 dione using the Oppenauer oxidation procedure; and

(C) converting said 17a-alkanoylaminopregn 4 ene- 3,20-dione to l7a-aminopregn-4-ene-3,20-dione by hydrolysis of the alkanoylamino group to remove the R and R are each hydrogen or methyl;

R is hydrogen or R75, where R; is a lower alkyl, cycloalkyl, phenyl, benzyl, substituted phenyl or substituted benzyl group; and 5 R and R are each hydrogen or lower alkanoyl; except that R cannot be hydrogen when R is hydrogen.

5. A compound of the structure: alkanoyl substituent.

10 7. The process of claim 6 wherein the starting material (5:34 used is N acetyl-16a, 17a-iminopregnen-5-en-3;8-ol-20 one.

alkanoylaminopregn-4-ene-3,20-dione is converted to the 17a-aminopregn-4-ene-3,20-dione by (l) heating a solution of said 17a-acetylaminopregn- 20 4-ene-3,20-dione in an aromatic hydrocarbon solvent with a strong acid and ethylene glycol to obtain the wherein: 17a-acety1amino-3,3-ethylenedioxy-5-en-20-one;

(2) reducing the latter compound with sodium borohydride to give 17u-acetylamino-3,S-ethylenedioxy- ImNHRi 8. The process of claim 6 wherein the mercaptan used Rl in Step A of the process is thiophenol, and the unsaturat- 15 ed hydrocarbon is cyclohexene.

9. The process of claim 6 wherein in Step C the 17m- Qi [0 I R and R are each hydrogen or methyl;

11: hydrogen or lower alkanoyl; and pregn 5 en 20g ol;

(3) hydrolyzing said 17a-acetylamino-3,3-ethylene-di- 0H oxypregn-S-en-ZO-ol with an inorganic base to the frf 17a-amino 3,3 ethylenedioxypregn-5-en-20-ol; and 1 then H (4) oxidizing said 170: amino-3,3-ethylenedioxypregnor :0. 5-en-20-ol with chromic acid to yield said 17ot-aminopregn-4-ene-3,20-dione. 6. A process for preparing the A compounds of 01am 1 where R; and R are each hydrogen or methyl and R References Cit d is hydrogen, which comprises the steps of (A) converting a N-alkanoyl 16m,17a-iminopregn-5- UNITED STATES PATENTS en-318-ol-20-one to a 17a-alkanoylaminopregn-5-en- 3,187,022 6/1965 Morrow 260--397.3

3fi-ol-20-one by heating with an alkali metal salt of a mercaptan having the formula R SH, where R-, is ELBERT ROBERTS, Pnmary Exammer an alkyl, phenyl, benzyl, substituted phenyl or substi- U S Cl X R tuted benzyl group, in an inert atmosphere to aiford the corresponding 16/3-R S-l7a-alkanoylaminopregn- 260397.3, 397.4, 999

S-cn-Sfi-ol-ZO-one, and then removing the R 8 group 

